Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1, 4-naphthoquinones through molecular modelling

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.

Complejos de vanadio (III) con glutatión en disolución acuosa / Vanadium (III) complexes with glutathione in aqueous solution

Se presentan los resultados del estudio de los complejos de vanadio(III) con glutatión (GSH, H3L) a 25 °C y en KCl3,0 M mediante medidas de fuerzas electromotrices, emf(H). El análisis de los datos mediante el programa de mínimos cuadrados generalizados LETAGROP indica la formación de cantidades significativas de los complejos VH4l4+, VH3L3+, V(H3L)23+ yv(L)(3L)2+, cuyas constantes de estabilidad fueron determinadas.

The formation of the vanadium(III) complexes with glutathione (GSH, H3L) was studied in 3.0 M KCl at 25 °C by means of electromotive forces measurements, emf (H). The analysis of the potentiometric data by means of the least-squares program LETAGROP indicates the formation of significant quantities of the complexes VH4l4+, VH3L3+, V(H3L)23+ yv(L)(3L)2+, whose stability constants were determined.